Appraising epidemiology data and antimicrobial resistance of urinary tract infections in critically ill adult patients: a 7-year retrospective study in a referral Brazilian hospital

ABSTRACT BACKGROUND: Urinary tract infections (UTI) are highly preventable and have significant clinical and financial impact on the patient and the health care system. OBJECTIVE: To investigate UTIs in critically ill adult patients and the relationship of antimicrobial consumption and multidrug-resistant isolate. DESIGN AND SETTING: A cohort study performed in a Brazilian tertiary-care university hospital in the city of Uberlandia (MG), located at the Federal University of Uberlandia, southeast region of the country. METHODS: We analyzed a cohort of 363 patients with first episode of UTIs from the adult intensive care unit (ICU), from January 2012 to December 2018. The daily doses of antimicrobial administered were calculated. RESULTS: The incidence rate of UTI was 7.2/1000 patient days, with 3.5/1000 patient-days of bacteriuria, and 2.1/1000 patient-days of candiduria. Of 373 microorganisms identified, 69 (18.4%) were Gram-positive cocci, 190 (50.9%) Gram-negative bacilli, and 114 yeasts (30.7%). Escherichia coli and Candida spp. were the most common. Patients with candiduria had higher comorbidity score (Charlson Comorbidity Index ≥ 3), longer length of stay (P = 0.0066), higher mortality (P = < 0.0001) severe sepsis, septic shock, and were immunocompromised when compared with patients with bacteriuria. We observed correlation between antibiotics consumption and multidrug-resistant (MDR) microorganisms. CONCLUSION: The UTIs incidence was high and was mainly caused by Gram-negative bacteria that were resistant to common antibiotics. We observed increase in the consumption of broad-spectrum antibiotics in ICU correlating with MDR microorganisms. In general, ICU-acquired candiduria may be associated with critical illness and poor prognosis.


INTRODUCTION
Urinary tract infections (UTI) are the most frequently reported healthcare associated infection (HAI), accounting for up to 40% of all HAIs. 1,2 The risk of these infections increases with hospitalization in intensive care units (ICUs), where incidence rates range between 15.5% and 37.6% in low-and middle-income countries, such as Brazil. [3][4][5] UTI is closely correlated with use of indwelling urinary catheters HAIs, 1,2 and according to the Centers for Disease Control and Prevention approximately 75% of UTIs have this association. 6 In countries, such as Brazil UTI continue to prevail and represent a major safety concern for patients. 5,7 It is estimated that in Brazil, 16.6% to 37.6% of all ICU-acquired infections are UTI resulting in 10.7%-20.0% related deaths. 3,4,8,9 Two important aspects about these infections are: (I) in recent years the frequent use of antibiotics in the treatment of asymptomatic infections, has resulted in the urinary tract becoming a major reservoir of resistant pathogns; 10,11 and (II) these infections can be associated with secondary bloodstream infections (BSI), an infection that develops subsequent to a documented infection of the blood with the same organism. 12

OBJECTIVE
In this study, we investigated the characteristics of patients and microorganisms involved in UTIs in critically ill adult patients and the relationship of antimicrobial consumption and the number of multidrug-resistant (MDR) isolate.

Statistical analysis
The Chi-square tests or Fisher's exact test were used to compare discrete variables. Fisher's exact test was used instead of the Chisquare test when one or more expected values in the 2 × 2 contingency table were equal or less than 5. The comparison of two quantitative variables was made using the Mann-Whitney test for nonparametric variables and the Students-t test for parametric variables. Two-sided tests were used for all analyses. All P value < 0.05 was considered statistically significant. The Pearson's correlation coefficient test was used to describe the relation-

During a 7-year period (2012-2018), a cohort of 363 critical
patients with first episode of UTI were included in the study, of these 252 (69.4%) were caused by bacteria and 109 (30.0%) by Candida sp. Further, two episodes of infection had a fungal etiology of the genus Trichosporon (0.5%), and these were not included in the comparative analyzes between bacteriurias and candidurias. The incidence rate of UTI was 7.2/1000 patient-days with 3.5/1000 patient-days for bacteriuria and 2.1/1000 patientdays for candiduria ( Table 1). Overall, only 10/363 (2.7%) episodes were polymicrobial.
The average length of hospitalization and that after diagnosis were prolonged, 15 (standard deviation [SD] ± 13.29) and 11 days (SD ± 12.52), respectively. The crude mortality rate was 38.8% and was more frequently among those with candiduria (55.0%) than those with bacteriuria (31.3%; Table 2).
There was significant difference in patient characteristics between those with bacteriuria and candiduria. The patients with candiduria were women (68.6%, P = 0.0086), older (58.3 years, SD 58.35 ± 20.55, P = < 0.0001), had more severe illness, had diabetes mellitus (P = 0.0012) and nephropathy (P = 0.0014), with presence of septic shock (P = 0.0002). Moreover, patients with candidemia showed more ICU-LOS than those with bacteriuria, > 15 days (62.3% versus 46.8%, P = 0.0066). Furthermore, traumatic patients were most frequently observed in the group of patients with bacteriuria (P = 0.0034). In addition, high frequency of mechanical ventilation in both groups was observed; however, it was not statistically significant ( Table 2). Majority of the patients were using a bladder catheter (90.9%) for a longer period, with an average of 13 days (SD ± 13.29;

DISCUSSION
In this retrospective analysis, we attempted to investigate the characteristics of critical patients with candiduria and bacteriuria and the relationship of antimicrobial consumption and the  severe sepsis, septic shock, and were immunocompromised when compared with patients with bacteriuria. Higher incidence of mortality and a longer ICU-LOS, as reported in another study, 17 was also observed.
The overuse and misuse of antimicrobials in hospital settings, has caused increased bacterial resistance over time, particularly in lower and middle-income countries. 3,4,17,24 In Brazil, a rising number of scientific articles have shown high frequencies of bacterial resistance especially among infections due to K. pneumoniae, P. aeruginosa, and A. baumannii. 3,4 Historically, the literature describes the urinary tract as a reservoir of MDR microorganisms. 25,26 These microorganisms were common in our cohort; High rate of occurrence of bacteria from the Enterobacteriaceae family and Candida spp., especially C. albicans (57.0%) was observed. This increase in fungal infections has been reported by other studies. 17 The impact of antibiotic therapy on microbiological ecology contributes to the emergence of these pathogens. In addition, a high frequency of E. faecalis was also found among Gram-positive species (43.4%). This is an interesting finding, since in developing countries and particularly in Brazil, these infections are primarily caused by GNB. 24 Moreover, in this cohort we found alarming frequencies of MDR A. baumannii and P. aeruginosa strains, as well as high intensity consumption of the broad-spectrum cephalosporins followed by carbapenems. In addition, positive correlation was found between the consumption of polymyxin B and meropenem with multidrug-resistant infections. This positive correlation between carbapenems and MDR infections was also demonstrated in other studies. 27,28 In general, the quantity of antibiotics for general use in the evaluated ICU was higher than that compared to other countries. [29][30][31] Our results reinforce that the ICU is a favorable environment for the emergence of resistant microorganisms, and it is necessary for countries to invest in strategies to prevent these infections. Likewise, the importance of urine as a source of these phenotypes has also been demonstrated.
Although unexpected, we found a high mortality rate in our cohort (38.8%); however, this was attributed to several factors, such as BSI occurring concomitantly or after UTIs and the severity of acute clinical diseases. As previously mentioned, Candida sp. were very common in our investigation and patients with candiduria had higher mortality rates. Thus, our results suggest an association between candiduria and increased patient morbidity, which is likely to be a marker of patient severity, as noted by Horan et al. 16 Figure 1. Relationship between the defined daily dose of antimicrobials per 1.000 patient-days and the number of patients with multidrug-resistant urinary tract infections per 1.000 patient day in the intensive care unit of hospital.

CONCLUSION
In conclusion, the data presented in this report fortify the fact that UTIs caused by MDR GNB organisms and Candida sp. in adult ICUs are a challenge for the patient safety. The UTI rates and the consumption of antimicrobials found in our study were higher than that from of countries. Better strategies for the effective and systematic surveillance and prevention of this problem is required for greater adherence to infection control measures and antimicrobials use in ill patients.